Cardiac remodeling is a complex process that results in structural and functional changes in one or more chambers in the heart, especially the ventricles. Macroscopically, such changes lead to an increase in end-diastolic and end-systolic volume, an alteration in the shape of the heart from ellipsoid to a more spherical form, and cardiac hypertrophy, most notably an increase in the left ventricular mass (LV mass). Remodeling can occur essentially after any insult to the myocardium and is a progressive and self-perpetuating process that involves a period of myocellular hypertrophy, followed by an absolute reduction in cell number. Following an insult, genomic changes resulting from the insult lead to subsequent molecular, cellular and interstitial changes, leading to the structural alterations discussed above, and is manifested clinically as changes in the size and function of the heart. As such, cardiac remodeling is a significant contributor to cardiac diseases, such as the development and progression of congestive heart failure. Cardiac remodeling can also lead to arrhythmias and sudden death, such as those caused by cardiac dysrhythmia.
Congestive heart failure is one of the most significant causes of morbidity and mortality in developed countries. It occurs as a late manifestation in diverse cardiovascular diseases characterized by loss of contractile mass and/or by volume or pressure overload (Fortuno, Hypertension 38: 1406-1412 (2001)). Numerous studies have proposed that cardiac remodeling is a major determinant of the clinical course of CHF, irrespective of its etiology (Fedak, Cardiovascular Pathology 14:1-11 (2005)). Cardiac remodeling is thus an attractive target for the treatment of congestive heart failure. As such, agents that act to prevent or decrease cardiac remodeling are desired. Indeed, the literature has identified a need for molecules that can attenuate cardiac remodeling (Fortuno, Hypertension 38:1406-1412 (2001)). Literature reports indicate that attenuating ventricular remodeling also improves survival after myocardial insult, while treatments which worsen remodeling have been associated with poorer outcomes even when they improve systolic function (See, Somasundaram, Med. Clin. N. Am., 88: 1193-1207 (2004)).
Literature reports indicate that GLP-1 released from gut endocrine L cells is a regulator of the phosphoinositide 3-kinase in pancreatic β-cells (Buteau, Diabetologica 42:856-864 (1999)). This kinase has been associated with myocardial protection in ischemic/reperfusion injury and myocardial preconditioning settings (See e.g., Bose, et al., Diabetes 54: 146-151 (2005)). More particularly, GLP-1 has been used to prevent myocardial infarction in isolated and intact rat heart (See id). According to the literature, GLP-1 released from the pancreas acts by activating a GLP-1 receptor, one such receptor has been identified as a 463-amino acid member of the G protein-coupled receptor superfamily (Drucker, Diabetes 47: 159-169 (1998)). It has been reported that a GLP-1 receptor in cardiac myocytes is structurally identical to the pancreatic islet receptor (See id.).
GLP-1 has been described in the treatment of certain cardiac conditions in U.S. Pat. No. 6,277,819, WO 99/40788, WO 01/89554, WO 03/084563, and WO/056313. However, until now, the use of cardioprotective incretin compounds (CICs), such as GLP-1, exendin, agonists and analogs thereof, to ameliorate, attenuate, delay, or prevent cardiac remodeling has not yet been described. Previous treatments of cardiac remodeling have included pharmaceutical, surgical and catheter-based interventions. Despite the ongoing research and development of treatments for cardiac remodeling, there is still a tremendous need for improved and alternative treatments.